Neural Mechanisms Underlying

Hallucinations in Schizophrenia:
The Role of Abnormal
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Fronto-Temporal Interactions
Emily Stern and David Silbersweig

H allucinations are a prominent and debilitating psychotic symptom

of schizophrenia. They usually take the form of voices talking to
or about the patient, often in a derogatory fashion. With increased
severity of illness, other modalities, such as visual and tactile, may be
involved. Up to 75% of patients experience such involuntary percepts
in the absence of external stimuli at some point in their illness (Wing,
Cooper, & Sartorius, 1974). A striking feature of hallucinations in
schizophrenia, in contrast to those accompanying structural neurolog-
ical disorders, is that they often have affective, conceptual, and behav-
ioral relevance for the patient. Patients become emotionally involved
with their hallucinations, incorporate them into delusional belief sys-
tems, and may even act on them.
Given the predominantly auditory-linguistic form of schizophrenic
hallucinations, as well as the loss of reality testing associated with them,
superior temporal and prefrontal abnormalities might be postulated.
When considering the role that such neuroanatomical areas might play,
one must consider not only the information-processing characteristics
of individual subregions but also their pattern of afferent (incoming)
and efferent (outgoing) connections. This is consistent with the trend

235

http://dx.doi.org/10.1037/10305-009
Origins and Development of Schizophrenia: Advances in Experimental
Psychopathology, edited by M. F. Lenzenweger and R. H. Dworkin
Copyright © 1998 American Psychological Association. All rights reserved.
 STERN AND SILBERSWEIG

in behavioral neuroscience over the past decade of emphasizing the

distributed (rather than purely localized) nature of the neural substrates
of behavior (Mesulam, 1990). More recently, the neuropsychological
and neurophysiological importance of interactions among the regions
making up these parallel distributed systems has also been recognized
(Friston, Frith, Fletcher, Liddle, & Frackowiak, 1996).
Rapidly advancing functional neuroimaging technologies when
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combined with careful study design provide a means of localizing and

characterizing neuronal activity associated with human mental states.
Positron emission tomography (PET) is a particularly well-developed
method of assessing systems-level activity. The use of water (H,O) or
carbon dioxide (CO,), radiolabeled with a short half-life isotope of
oxygen ("O), allows multiple, repeated sampling of brain-mental states
in a single study session. These PET radiotracer techniques work by
measuring the regional cerebral blood flow changes coupled to local
synaptic activity. With high-sensitivity %dimensional scanning, specific
psychological or psychiatric activation paradigms, and appropriate uni-
variate and multivariate image analysis techniques, statistically signifi-
cant results can be obtained with single subjects or with groups (Frac-
kowiak & Friston, 1994).
We and our colleagues have performed a series of PET studies fo-
cusing on the problem of hallucinations in schizophrenia. These studies
use new ''0 activation methodologies that extend previous single pho-
ton emission computed tomograph and PET approaches (reviewed else-
where, see Silbersweig & Stern, 1996) to this problem. Here, we discuss
our studies in the context of fronto-temporal interactions and their
implications for symptom formation. The studies converge on the psy-
chopathophysiological issues, starting with a consideration of schizo-
phrenia as an overall diagnostic syndrome, progressing to an assessment
of trait characteristics that predispose to hallucinations in schizophre-
nia, and ending with an analysis of the specific hallucinating state in
schizophrenia. The syndrome and trait studies use a top-down
approach-starting with some of the neuropsychological processes
thought to be disrupted, scanning normal subjects and patients during
appropriately designed activation and control tasks that isolate those

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 NEURAL MECHANISMS

processes, and contrasting the brain images associated with those tasks
to localize symptomatically relevant dissociations in brain activity. In
contrast, the state study uses a bottom-up approach-directly mapping
the neural substrates of the symptom and interpreting the results in
light of behavioral neuroscientific principles. These investigationalstrat-
egies are complementary and may inform one another (Silbersweig &
Stern, 1996). The design and pertinent results of each study are outlined
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below, followed by a discussion of the pathophysiological implications

of abnormal activity in and interactions between frontal and temporal
regions.

PET STUDIES
Words are generated by patients with schizophrenia during auditory-
verbal hallucinations, even if the patients attribute them to another
source. Word generation therefore involves a set of neuropsychological
functions of relevance to the linguistic aspects of typical schizophrenic
hallucinations. Eighteen chronic, medicated patients with schizophrenia
(divided into three groups of six, on the basis of verbal fluency per-
formance) and six age, sex, premorbid IQ-matched normal control sub-
jects were studied with a paced word-generation, PET-activation para-
digm (Frith et al., 1995). The activation task involved generating words
starting with a given letter. One letter was presented aurally every 5 s.
A given letter was repeated 10 times unless the individual failed to
generate an appropriate word, in which case a new letter was presented.
The sensory-motor control task involved the presentation of the same
type of stimuli, but the subject was instructed to merely repeat the letter
aloud (thereby controlling for auditory input and speech output). Im-
ages from each condition were processed and analyzed (contrasted)
with statistical parametric mapping (SPM) techniques.
In the word-generation condition versus the control condition, nor-
mal subjects activated a distributed cortical-subcortical system, includ-
ing the left dorso-lateral prefrontal cortex, anterior cingulate, and thal-
amus.Areas of relatively decreased activity for this comparison included
the superior temporal cortices (left greater than right). Patients with

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 STERN AND SILBERSWEIG

schizophrenia, regardless of task performance, were able to activate the

frontal regions. However, these patients did not show decreased activity
in the superior (and, to a lesser extent, middle) temporal cortices. In
fact, with a canonical variates analysis (capable of identifymg distrib-
uted patterns of neural activity accounting for the experimentally in-
duced variance), the patients showed increased activity in these tem-
poral regions.
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Instead of examining the overall syndrome of schizophrenia, the

next study focused on the symptom trait-the predisposition to hal-
lucinate. The neuropsychological tasks used in this study probed the
processes of inner speech and auditory-verbal imagery. Covert speech
has been implicated in schizophrenic hallucinations, given the possible
disruption of normal linguistic thought processes and the variable find-
ing of subvocal speech (detected with throat microphones) in some
hallucinating patients that matched the reported content of their
“voices” (Gould, 1949). Auditory-verbal mental imagery is another im-
portant process to consider. Like hallucinations, imagery represents per-
ception in the absence of external stimuli; but unlike hallucinations
(which are involuntary), it is under voluntary control.
Three groups of six subjects each were studied in this experiment
-patients with schizophrenia and a history of hallucinations (trait pos-
itive but not currently hallucinating), patients with schizophrenia and
no history of hallucinations (trait negative, patient controls), and nor-
mal controls (McGuire et al., 1995; McGuire, Silbersweig, Wright, et al.,
1996). All groups were matched for age and premorbid IQ. Patients
were also matched for illness duration and neuroleptic dose (in chlor-
promazine equivalents). Three tasks were performed in a counterbal-
anced order (to counteract time and order effects). The contrast of Task
2 versus Task 1 isolated inner (silent) speech, whereas the contrast of
Task 3 versus Task 2 isolated auditory-verbal imagery.
In this experiment, there was no difference in the functional neu-
roanatomy of inner speech (including Broca’s area) between the schizo-
phrenia patients with a predisposition to hallucinate and the control
groups. There was, however, a difference in the auditory-verbal imagery
condition. Whereas normal and patient controls showed increased ac-

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 NEURAL MECHANISMS

tivity in bilateral rostral supplementary motor cortex (in the superior

medial frontal lobe) and left middle temporal gyrus, schizophrenia pa-
tients with a hallucination trait actually showed decreased activity in
these regions.
To map the neural substrates of hallucinations in a direct bottom-up
fashion, we developed and validated new techniques of PET image ac-
quisition and analysis (Silbersweig et al., 1993, 1994). The increased sen-
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sitivity and temporal discrimination of these methods allowed the study

of such transient, randomly occurring symptoms in a naturalistic manner.
Five patients with schizophrenia and classic auditory-verbal hallucinations
despite medication and one drug naive patient with both visual and au-
ditory-linguistic hallucinations were studied (Silbersweig et al., 1995).
In the patient with visual and auditory-verbal hallucinations, prom-
inent activity was detected in visual and auditory-linguistic association
cortices and in posterior cingulate, parahippocampal/mesotemporal,
and temporal pole (para)limbic regions as well as in the striatum. The
neocortical and posterior cingulate activity was greater in the dominant
hemisphere, whereas the mesotemporal and subcortical activity was
greater in the nondominant hemisphere. In particular, brain areas pos-
itively correlated with hallucinations included left posterior superior
temporal gyrus (Wernicke’s area), left posterior cingulate gyrus, right
striatum, and visual and auditory association cortices. In contrast, brain
areas in which activity was negatively correlated with hallucinations
included right superior temporal gyrus, right posterior cingulate gyrus,
left striatum, bilateral prefrontal cortices, and primary visual and au-
ditory cortices (Silbersweig et al., 1996). The regions of activation com-
mon to the group of five patients with auditory-verbal hallucinations
were deep (para)limbic and subcortical structures, including the hip-
pocampus, parahippocampal gyrus, anterior cingulate gyrus, thalamus,
and ventral striatum. There were no prominent frontal activations in
these group analyses.

DISCUSSION
The studies described above demonstrate abnormal fronto-temporal ac-
tivity and functional connectivity (the temporal correlations between

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spatially remote neurophysiological events; Friston et al., 1996) in schizo-

phrenia in general and in association with hallucinations in particular.
These findings contribute to a growing awareness of such abnormalities
in schizophrenia (Friston & Frith, 1995; Weinberger, Aloia, Goldberg,
& Berman, 1994) and recall the origin of the disorder’s name (“split
mind”). The mechanisms underlying such aberrant activity are likely
to include abnormal mesolimbic dopaminergic modulation (Csernan-
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sky, Murphy, & Faustman, 1991) and an abnormal balance between

excitation and inhibition in local neuronal circuits (Benes, Vincent, Al-
sterberg, Bird, & San Giovanni, 1992; Olney & Farber, 1995).
One of the consequences of abnormal functional connectivity is a
failure of corollary discharge, or reafferent signaling. Corollary dis-
charge is the process by which information about an intended action
is transferred via direct or indirect connections from the efferent region
planning or producing the action to an afferent region, which would
receive sensory stimulation or feedback as a result of the action. A
disruption of this process in schizophrenia, as suggested by Frith (1987,
1996), could result in symptom formation when information about an
intended action is not properly monitored or interpreted (as a result
of faulty interactions between frontal behavioral regions and posterior
perceptual regions). For instance, delusions of control (or passivity)
could result when a self-generated movement is not associated with a
sense of volition and/or is mistakenly believed to arise from another
source, or both. In the case of hallucinations, self-generated verbally
mediated thoughts may similarly be misinterpreted as arising from an-
other source.
The “articulatory/phonological loop” working memory system
(Baddeley, 1992), localized to the left lateral frontal and temporoparietal
regions (Paulesu, Frith, & Frackowiak, 1993), is involved in the “on-
line” processing of such verbally mediated and monitored thought. An-
other way to conceive of the contribution of abnormal functional
connectivity to symptom formation (in the context of working
memory deficits in schizophrenia; Goldman-Rakic, 1994) would there-
fore be as a failure to transfer and update information between the
frontal and the temporoparietal components of the loop. This would

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 NEURAL MECHANISMS

result in a fragmentation of the stream of auditory-linguisticconscious

experience-a possible contributor to hallucinations.
In the word generation experiment, there was a lack of the normal
correlation between left dorso-lateral prefrontal activity and superior
temporal activity when patients with schizophrenia generated words
(there were temporal increases instead of normal decreases in the set-
ting of dorso-lateral prefrontal increases). Although this finding is not
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specific to patients with hallucinations, it may represent a predisposing

factor in light of the theories of symptom formation mentioned above.
The dorso-lateral prefrontal cortex is involved in generating volitional
behavior (Frith, Friston, Liddle, & Frackowiak, 1991; including speech),
and superior temporal cortex is involved in monitoring language (in-
cluding self-generated speech; McGuire, Silbersweig, & Frith, 1996).
Similarly, the inner speech/auditory-verbal imagery experiment demon-
strated a failure of normal activation of rostral supplementary motor
cortex and left middle temporal cortex in schizophrenia patients with a
trait for hallucinations. This medial frontal-middle temporal abnormal-
ity may be a more specific predisposing factor for hallucinations, signi-
fying a failure of volitionaVpreparatory control and semantic/source
monitoring of verbally mediated thought (McGuire et al., 1995).
More direct evidence of abnormal frontal and temporal activity was
obtained from the bottom-up PET experiments in which patients were
imaged in the hallucinating state. These studies showed prominent tem-
poral activations in the setting of an absence of, or even decrease in,
prefrontal activity- The subject analyzed individually had activations in
lateral (superior and middle) temporal regions, partially overlapping with
regions in which decreases were noted in the top-down, nonhallucinating
studies. Whereas the bottom-up studies are more specific to the problem
of hallucinations than the top-down studies, it is possible to reconcile
these results by postulating that regional abnormal balances of
excitation-inhibition result in phasic increases in brain activity in these
areas, superimposed on tonic decreased activity. This would not be sim-
ilar to the temporal pattern in seizure foci of patients with epilepsy.
The lateral temporal findings are interesting in light of the
auditory-linguistic functions of these regions. Certainly, normal subjects

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 S T E R N AND SILBERSWEIG

show activations in these areas during exposure to external auditory-

linguistic stimuli (outside voices) of the sort reported by hallucinating
schizophrenia patients (Silbersweig et al., 1993). Some of the specific
sensory content of hallucinations may therefore be determined by such
localized aberrant activity. From a mechanistic point of view, however,
the medial temporal activations may be even more important. This is
because they are so prominent in hallucinating patients yet absent when
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control subjects listen to or imagine voices. These hippocampal-

parahippocampal regions are highly interconnected with other limbic-
paralimbic structures as well as association cortices (Pandya & Yeterian,
1985), are involved in the recall or generation of sensory and semantic
representations (Schacter, Alpert, Savage, Rauch, & Albert, 1996), and
have abnormal morphology (Marsh, Suddath, Higgins, & Weinberger,
1994) and function (Friston, Liddle, Frith, Hirsch, 8r Frackowiak, 1992;
Liddle et al., 1992) associated with psychopathology in schizophrenia.
Such structures, together with interrelated thalamic and ventral striatal
circuits (which, although not emphasized here, are also likely to play a
central pathophysiologic role; Silbersweig & Stern, 1996), may therefore
be in a position to trigger the symptomatic events.
All of this appears to occur in the setting of a relative lack of pre-
frontal activity (although some frontal activations were present in indi-
vidual patients). Given the executive role of prefrontal structures as de-
scribed above, this hypofrontal-hypertemporal pattern may underlie the
lack of reality testing often exhibited by psychotic hallucinating patients.
Finally, preliminary analyses of the single subject activations suggest
that hallucinations are associated with more widespread abnormal pat-
terns of interregional correlations, including negative rather than pos-
itive right-to-left temporal correlations (Silbersweig et al., 1996). This
may result in a lack of balance and integration of linguistic and
paralinguistic components of verbal thought.

CONCLUSION
We have presented a number of related PET activation studies-
focusing with increasing specificity on the diagnosis of schizophrenia,

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 NEURAL MECHANISMS

the trait of hallucinations, and the hallucinating state-in which ab-

normalities in lateral and medial frontal activity as well as lateral and
medial temporal activity were noted. Possible mechanisms associated
with the pathogenesis of hallucinations were discussed in the context
of the neuropsychological functions of and functional connectivity
among these interconnected brain regions. Clearly, additional studies
are needed to replicate, clarify, and extend the findings mentioned here.
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More extensive multivariate analyses will also help to address the crucial
issue of the interactions, or correlations in activity, among brain regions
during hallucinations. In addition, the increased temporal resolution of
functional magnetic resonance imaging and magnetoencephalographic
methods will be important in determining the spatiotemporal sequence
associated with the triggering and spread of abnormal distributed ac-
tivity underlying symptom formation. Finally, the information gained
through functional neuroimaging research must be integrated with rel-
evant findings in cognitive neuropsychological and basic neuroscientific
studies to arrive at a comprehensive understanding of the problem of
hallucinations in schizophrenia. It is our hope that such an understand-
ing will not only provide insight into this fascinating and devastating
neuropsychological phenomenon but also provide a foundation for
more targeted, biologically based diagnostic and therapeutic strategies.

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